The prevalence of overweight has reached epidemic proportions in most developed countries and carries with it staggering mortality and morbidity statistics. Obesity is a well established risk factor for a number of potentially life-threatening diseases such as atherosclerosis, hypertension, diabetes, stroke, pulmonary embolism, and cancer. (Meisler J., St. Jeor S. 1996. Am J Clin Nutr. 63:409S-411S). (Bray G. 1996. Endocrin Metab Clin North Amer. 25:907-919). Furthermore, it complicates numerous chronic conditions such as respiratory diseases, osteoarthritis, osteoporosis, gall bladder disease, and dyslipidemias. The enormity of this problem is best reflected in the fact that death rates escalate with increasing body weight. More than 50% of all-cause mortality is attributable to obesity-related conditions once the body mass index (BMI) exceeds 30 kg/m2, as seen in 35 million Americans. (Lee L, Paffenbarger R. 1992. JAMA. 268:2045-2049). By contributing to greater than 300,000 deaths per year, obesity ranks second only to tobacco smoking as the most common cause of potentially preventable death. (McGinnis J., Foege W. 1993. MA.270:2207-22 12).
Accompanying the devastating medical consequences of this problem is the severe financial burden placed on the health care system in the United States. The estimated economic impact of obesity and its associated illnesses from medical expenses and loss of income are reported to be in excess of $68 billion/year. (Colditz G. 1992. Am J Clin Nutr. 55:503S-507S). (Wolf A., Colditz G. 1996. Am J. Clin Nutr. 63:466S-469S). (Wolf A., Colditz G. 1994. Pharmacoeconomics. 5:34-37). This does not include the greater than $30 billion per year spent on weight loss foods, products, and programs. (Wolf A., Colditz G. 1994. Pharmacoeconomics. 5:34-37). (Ezzati, et a. 1992. Vital health Stat [2]. 113).
In 1990, the US government responded to the crisis by establishing as a major national health goal the reduction in the prevalence of obesity to (20% of the population by the year 2000. (Public Health Service. Healthy people 2000: national health promotion and disease prevention objectives. 1990. (US Department of Health and Human Services Publication PHS 90-50212.))
In spite of this objective, the prevalence of overweight in the United States has steadily increased, reaching an astounding 33.0% in the most recent National Health and Nutrition Examination Survey (1988-1991). (Kuczmarski, et al. 1994. JAMA. 272:205-211). Furthermore, the mean BMI has also increased over this period by 0.9 kg/m2. This alarming trend has not occurred as the result of lack of effort. On the contrary, an estimated 25% of men, 50% of women, and 44% of adolescents are trying to lose weight at any given time. (Robinson, et al.J Amer Diabetic Assoc. 93:445-449). Rather, the 31% increase in rate and 8% increase in prevalence over the past decade is a testimony of the fact that obesity is notoriously resistant to current interventions. (NIH Technology Assessment Conference Panel. 1993. Ann Intern Med. 119:764-770).
A major reason for the long-term failure of established approaches is their basis on misconceptions and a poor understanding of the mechanisms of obesity. Conventional wisdom maintained that obesity is a self-inflicted disease of gluttony. Comprehensive treatment programs, therefore, focused on behavior modifications to reduce caloric intake and increase physical activity using a myriad of systems. These methods have limited efficacy and are associated with recidivism rates exceeding 95%.
Failure of short-term approaches, together with the recent progress made in elucidating the pathophysiology of obesity, have lead to a reappraisal of pharmacotherapy as a potential long-term, adjuvant treatment. (National Task Force on Obesity. 1996. JAMA. 276:1907-1915). (Ryan, D. 1996. Endo Metab Clin N Amer. 25:989-1004). The premise is that body weight is a physiologically controlled parameter similar to blood pressure and obesity is a chronic disease similar to hypertension. The goal of long-term (perhaps life long) medical therapy would be to facilitate both weight loss and subsequent weight maintenance in conjunction with a healthy diet and exercise. To assess this approach, the long-term efficacy of currently available drugs must be judged against that of non-pharmacological interventions alone. The latter approach yields an average weight loss of 8.5 Kg at 21 weeks of treatment and only maintains 50% of the weight reduction at 4 years in 10-30% of the patients. (Wadden T. 1993. Ann Intern Med. 119:688-693). (Kramer, et al.1989. Int J Obes. 13:123-136). The few studies that have evaluated long-term (greater than 6 months) single-drug (Guy-Gran, et al. 1989. Lancet. 2:1142-1144) (Goldstein, et al. 1994 Int J Obes. 18:129-135) (Goldstein, et al. 1993. Obes Res. 2:92-98) or combination therapy (Weintraub M. 1992. Clin Pharmacol. Ther. 51:581-585) show modest efficacy compared with placebo in the reduction of body weight.
All medications currently used to treat or prevent obesity are directed at the adipocyte compartment of the tissue and work by either decreasing energy availability or increasing energy output. These agents can be placed into three categories based on mechanism. (National Task Force on Obesity. 1996. JAMA. 276:1907-1915).
Reduction of energy intake. This approach is directed at reducing food intake by decreasing appetite or increasing satiety. These `anorexiant` drugs affect neurotransmitter activity by acting on either the catecholaminergic system (amphetamines, benzphetamine, phendimetrazine, phentermine, mazindol, diethylpropion, and phenylpropanolamine) or the serotonergic system (fenfluramine, dexfenfluramine, fluoxetine, sertraline, and other antidepressant selective serotonin reuptake inhibitors [SSRI]).
Reduction in absorption of nutrients: Drugs in this category block the action of digestive enzymes or absorption of nutrients. An example of this type of drug is orlistat which inhibits gastric and pancreatic lipase activity. (Drent M., van der Veen E. 1995. Obes Res. 3(suppl 4):623S-625S). These medications are experimental in the United States and not available for the treatment of obesity.
Increase in energy expenditure: An increase in energy expenditure may be accomplished by increasing metabolic rate, for example, through changes in sympathetic nervous system tone or uncoupling of oxidative phosphorylation. Drugs that affect thermogenesis-metabolism include ephedrine alone and in combination with caffeine and/or aspirin, (Passquali R., Casimirri F. 1993 Int J Obes. 17(suppl 1):S65-S68) and BRL 26830A, a (-adrenoceptor agonist. (Connacher, et al. 1992. Am J Clin Nutr. 55:258S-261S). This class of medications is not approved by the FDA for weight control.
Currently, no single drug regimen emerges as superior in either promoting or sustaining weight loss.
Surgical interventions, such as gastric partitioning procedures, jejunoileal bypass, and vagotomy, have also been developed to treat severe obesity. (Greenway F. 1996. Endo Metab Clin N Amer. 25:1005-1027). Although advantageous in the long run, the acute risk benefit ratio has reserved these invasive procedures for morbidly obese patients according to the NIH consensus conference on obesity surgery (BMI greater than 40 kg/m2). (NIH Conference. 1991. Ann Intern Med. 115:956-961). Therefore, this is not an alternative for the majority of overweight patients unless and until they become profoundly obese and are suffering the attendant complications.
There is no medical or surgical treatment for obesity that is directed at the vascular compartment of the tissue.
It is therefore an object of the present invention to provide a treatment to reduce obesity.
It is a further object of the present invention to provide compositions for treatment of obesity.
It is another object of the present invention to provide methods for inhibiting or decreasing overproliferation of other normal, vascularized tissues.